Amyloid plaques are a major pathological hallmark of Alzheimer's disease. The principle component of amyloid plaques, A.beta.,.sup.1 is derived by proteolytic processing of the Alzheimer amyloid protein precursor (APP).sup.2,3. APP is a Type I integral membrane protein expressed as three major alternatively spliced isoforms of 695, 751 and 770 amino acids in length. The 695 amino acid isoform is most abundant in neurons. APP is processed in two pathways by at least three unidentified proteases known as the .alpha.-, .beta.- and .gamma.-secretases..sup.4-6 A.beta. is generated from cleavage by both .beta.- and .gamma.-secretase. .alpha.-secretase cleaves APP within the A.beta. domain, precluding A.beta. formation. The majority of processed APP is cleaved by .alpha.-secretase, releasing the large extracellular domain referred to as APPs. Both APPs and A.beta. are secreted by normal cells..sup.4-8 However, the cells in Alzheimer patients abnormally allow the aggregation and accumulation of A.beta., and thus facilitate the formation of the amyloid plaques.
Fe65 is a brain-enriched protein of unknown function which binds to the NPTY sequence in the cytoplasmic tail of APP..sup.9-11 Fe65 contains two types of protein-protein interaction domains, the WW domain and the PI domain, binding APP through the second of its two PI domains.